Abstract
AIMS: Endothelin is a peptide produced by endothelial cells with many biological properties. In the human skin microcirculation endothelin induces neurogenic vasodilation associated with burning pruritus. We investigated the mechanisms involved in this response. METHODS: The effects of prolonged pretreatment with capsaicin, a specific inhibitor of polimodal nociceptor fibres, and of the nitric oxide synthase inhibitor L-NMMA on endothelin-1-induced vasodilation were studied in 15 human subjects. Furthermore, we investigated the effects of the ET(A)-selective antagonist PD147953 on bradykinin-induced vasodilation. RESULTS: After local injection, endothelin-1 caused vasoconstriction at the injection site and a profound vasodilation in the surrounding area (flare reaction, P<0.01). This response was specific and not induced by saline, albumin, acetylcholine or an ET-antagonist. Prolonged capsaicin pretreatment inhibited endothelin-1 induced vasodilation in the area surrounding the injection site, but not the central vasoconstriction at the injection site. Bradykinin also induced a marked vasodilation in the area surrounding the injection site; this was not inhibited by an ETA-selective antagonist, while the flare reaction was. L-NMMA applied at the site of the flare reaction prevented endothelin-1-induced vasodilation. CONCLUSIONS: Endothelin-1 in the human skin microcirculation stimulates polimodal nociceptor fibres leading to the release of nitric oxide. This response may play a pathophysiological role in inflammatory processes in the human skin.